Methods for producing autologous immune cells resistant to myeloid-derived suppressor cells effects
Patent Number: US8741642
Executive Summary:
General Description:
This invention is an improved method for the ex vivo differentiation and expansion of tumor-primed immune cells that are resistant to the effect of immune suppressor cells, such as myeloid-derived suppressor cells (MDSCs). MDSCs are one of the major barriers in the immunotherapy of breast cancer. Cancer patients have increased MDSCs due to the presence of cancer, and MDSCs suppress anti-tumor T cells. Therefore, cancers that fight the immune system by increasing MDSCs – such as breast cancer – can be treated by this protocol.
Scientific Progress:
The protected effect of reprogrammed T-cells generated with this protocol against tumor development and relapse was demonstrated in a mouse model of breast carcinoma. Moreover, the results of pilot study showed the clinical applicability of the protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients.
Future Directions:
Strengths:
Weaknesses:
Patent Status:
Legal Status: Active
Publication PMID: 18979098, 19826947, 21304453, 21670315, 20480224, 24197563
Publications:
Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH. Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2009 Jun;58(6):941-53. doi: 10.1007/s00262-008-0609-z. Epub 2008 Nov 1.
Cha E, Graham L, Manjili MH, Bear HD. IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo. Breast Cancer Res Treat. 2010 Jul;122(2):359-69. doi: 10.1007/s10549-009-0573-0. Epub 2009 Oct 14.
Kmieciak M, Toor A, Graham L, Bear HD, Manjili MH. Ex vivo expansion of tumor-reactive T cells by means of bryostatin 1/ionomycin and the common gamma chain cytokines formulation. J Vis Exp. 2011 Jan 14;(47). pii: 2381. doi: 10.3791/2381.
Kmieciak M, Basu D, Payne KK, Toor A, Yacoub A, Wang XY, Smith L, Bear HD, Manjili MH. Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol. 2011 Jul 15;187(2):708-17. doi: 10.4049/jimmunol.1100502. Epub 2011 Jun 13.
Kmieciak M, Worschech A, Nikizad H, Gowda M, Habibi M, Depcrynski A, Wang E, Godder K, Holt SE, Marincola FM, Manjili MH. CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer. Breast Cancer Res Treat. 2011 Apr;126(2):385-94. doi: 10.1007/s10549-010-0942-8. Epub 2010 May 18.
Payne KK, Zoon CK, Wan W, Marlar K, Keim RC, Kenari MN, Kazim AL, Bear HD, Manjili MH. Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res Treat. 2013 Nov;142(1):45-57. doi: 10.1007/s10549-013-2733-5. Epub 2013 Oct 25.
Inventor Bio: Masoud H. Manjili
http://www.medschool.vcu.edu/expertise/detail.html?ID=609
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: US Grant
- Patent Link: https://patents.google.com/patent/US8741642/
- Research Institute: Virginia Commonwealth University
- Disease Focus: Cancers, particularly breast cancer and melanoma, and infectious diseases
- Basis of Invention: Ex vivo generation of T-cells for use in adoptive cell transfer (ACT)
- How it works: Exposing tumor-primed T-cells obtained from a breast cancer or a melanoma patient to bryostatin and ionomycin (B/I), then to a combination of cytokines (IL-7, IL-15 and then IL-2)
- Lead Challenge Inventor: Masoud H. Manjili
- Inventors: Harry D. Bear, Maciej Kmieciak, Masoud H. Manjili
- Development Stage: Ex vivo expansion of human tumor-primed T-cells
- Novelty: Novel cytokine formulation to generate immune cells that are refractory to immune suppressive function of myeloid-derived suppressor cells (MDSCs)
- Clinical Applications: Treatment of breast cancer and melanoma
General Description:
This invention is an improved method for the ex vivo differentiation and expansion of tumor-primed immune cells that are resistant to the effect of immune suppressor cells, such as myeloid-derived suppressor cells (MDSCs). MDSCs are one of the major barriers in the immunotherapy of breast cancer. Cancer patients have increased MDSCs due to the presence of cancer, and MDSCs suppress anti-tumor T cells. Therefore, cancers that fight the immune system by increasing MDSCs – such as breast cancer – can be treated by this protocol.
Scientific Progress:
The protected effect of reprogrammed T-cells generated with this protocol against tumor development and relapse was demonstrated in a mouse model of breast carcinoma. Moreover, the results of pilot study showed the clinical applicability of the protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients.
Future Directions:
- Clinical trials
Strengths:
- Novel T-cell culture protocol to overcome MDSCs
Weaknesses:
- Many other ACT protocols to compete with. No standardization
Patent Status:
Legal Status: Active
- Priority date: 2010.10.22
- Filing date: 2011.10.21
- Publication date: 2014.06.03
- Grant date: 2014.06.03
Publication PMID: 18979098, 19826947, 21304453, 21670315, 20480224, 24197563
Publications:
Morales JK, Kmieciak M, Graham L, Feldmesser M, Bear HD, Manjili MH. Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2009 Jun;58(6):941-53. doi: 10.1007/s00262-008-0609-z. Epub 2008 Nov 1.
Cha E, Graham L, Manjili MH, Bear HD. IL-7 + IL-15 are superior to IL-2 for the ex vivo expansion of 4T1 mammary carcinoma-specific T cells with greater efficacy against tumors in vivo. Breast Cancer Res Treat. 2010 Jul;122(2):359-69. doi: 10.1007/s10549-009-0573-0. Epub 2009 Oct 14.
Kmieciak M, Toor A, Graham L, Bear HD, Manjili MH. Ex vivo expansion of tumor-reactive T cells by means of bryostatin 1/ionomycin and the common gamma chain cytokines formulation. J Vis Exp. 2011 Jan 14;(47). pii: 2381. doi: 10.3791/2381.
Kmieciak M, Basu D, Payne KK, Toor A, Yacoub A, Wang XY, Smith L, Bear HD, Manjili MH. Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol. 2011 Jul 15;187(2):708-17. doi: 10.4049/jimmunol.1100502. Epub 2011 Jun 13.
Kmieciak M, Worschech A, Nikizad H, Gowda M, Habibi M, Depcrynski A, Wang E, Godder K, Holt SE, Marincola FM, Manjili MH. CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer. Breast Cancer Res Treat. 2011 Apr;126(2):385-94. doi: 10.1007/s10549-010-0942-8. Epub 2010 May 18.
Payne KK, Zoon CK, Wan W, Marlar K, Keim RC, Kenari MN, Kazim AL, Bear HD, Manjili MH. Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells. Breast Cancer Res Treat. 2013 Nov;142(1):45-57. doi: 10.1007/s10549-013-2733-5. Epub 2013 Oct 25.
Inventor Bio: Masoud H. Manjili
http://www.medschool.vcu.edu/expertise/detail.html?ID=609
